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Int. J. Mol. Sci. 2018, 19(4), 1173;

Response of Myeloid Leukemia Cells to Luteolin is Modulated by Differentially Expressed Pituitary Tumor-Transforming Gene 1 (PTTG1) Oncoprotein

Center of Medical Genetics, Buddhist Tzu Chi General Hospital, Hualien 970, Taiwan
Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 970, Taiwan
Department of Ophthalmology, Kaohsiung Armed Force General Hospital, Kaohsiung 804, Taiwan
Department of Pharmacy, Kaohsiung Armed Force General Hospital, Kaohsiung 804, Taiwan
Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan
Author to whom correspondence should be addressed.
Received: 21 March 2018 / Revised: 8 April 2018 / Accepted: 9 April 2018 / Published: 12 April 2018
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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Luteolin, a flavonoid nutraceutical abundant in vegetables and fruits, exhibits a wide range of bioactive properties, including antioxidant, anti-inflammatory and anti-cancer activities. Pituitary tumor-transforming gene 1 (PTTG1), an oncoprotein that regulates cell proliferation, is highly expressed in several types of cancer cells including leukemia. In this study, we aim to investigate the anti-cancer effects of luteolin on cells with differential PTTG1 expression and their underlying mechanisms in human myeloid leukemia cells. Methyl thiazolyl tetrazolium (MTT) assay data showed that luteolin (25–100 μM) significantly reduced cell viability in THP-1, HL-60 and K562 cells but did not affect normal peripheral blood mononuclear cells (PBMCs). Flow cytometric analysis and Western blot data demonstrated that luteolin induced a stronger apoptosis on undifferentiated myeloid leukemia cells with higher PTTG1 protein levels than on 12-myristate 13-acetate (PMA)- or all-trans-retinoic acid (ATRA)-differentiated cells with lower PTTG1 expression. Furthermore, PTTG1 knockdown by shRNA in leukemia cells suppressed cell proliferation, arrested cell-cycle progression and impaired the effectiveness of luteolin on cell-cycle regulation. Moreover, PTTG1-knockdown cells with luteolin exposure presented a reduction of the apoptotic proteins and maintained higher levels of the anti-apoptotic proteins such as Mcl-1, Bcl-2 and p21, which exhibited greater resistance to apoptosis. Finally, microarray analysis showed that 20 genes associated with cell proliferation, such as CXCL10, VEGFA, TNF, TP63 and FGFR1, were dramatically down-regulated in PTTG1-knockdown cells. Our current findings clearly demonstrate that luteolin-triggered leukemic cell apoptosis is modulated by the differential expression of the PTTG1. PTTG1 oncoprotein overexpression may modulate cell proliferation-related regulators and enhance the response of myeloid leukemia cells to luteolin. Luteolin is beneficial for the treatment of cancer cells with highly expressed PTTG1 oncoprotein. View Full-Text
Keywords: luteolin; PTTG1; myeloid leukemia cells; apoptosis; cell proliferation luteolin; PTTG1; myeloid leukemia cells; apoptosis; cell proliferation

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Chen, P.-Y.; Tien, H.-J.; Chen, S.-F.; Horng, C.-T.; Tang, H.-L.; Jung, H.-L.; Wu, M.-J.; Yen, J.-H. Response of Myeloid Leukemia Cells to Luteolin is Modulated by Differentially Expressed Pituitary Tumor-Transforming Gene 1 (PTTG1) Oncoprotein. Int. J. Mol. Sci. 2018, 19, 1173.

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